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Repeated hypoglycemia in diabetic mice induce hypothalamic mitochondrial and synaptic activity deregulations characteristic of neurodegenerative diseases

ABSTRACT: Repeated exposures to insulin-induced hypoglycemia in diabetic patients progressively impair the counter-regulatory response (CRR) that restores normoglycemia. This defect is characterized by reduced secretion of glucagon and other counter-regulatory hormones. Evidence indicates that glucose responsive neurons located in the hypothalamus, orchestrate the CRR. Here, we aimed at identifying the changes in hypothalamic gene and protein expression that underlie impaired CRR. High fat diet fed and low dose streptozocin-treated C57BL6N mice were exposed to one (acute hypoglycemia, AH) or multiple (recurrent hypoglycemia, RH) insulin-induced hypoglycemic episodes. Single nuclei RNA sequencing (snRNAseq) data were obtained from the hypothalamus and cortex of AH and RH mice. Proteomic data were also obtained from hypothalamic synaptosomal fractions. The present study shows that repeated moderate hypoglycemia in diabetic mice lead, in the hypothalamus, to multiple cellular physiology changes, affecting all cell types and their interactions, which show striking features of neurodegenerative diseases. It also shows that repeated hypoglycemic episodes affect very differently the hypothalamus and the cortex.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Hypothalamus

DISEASE(S): Type 2 Diabetes Mellitus

SUBMITTER: Patrice Waridel

LAB HEAD: Bernard Thorens

PROVIDER: PXD040183 | Pride | 2023-11-13

REPOSITORIES: Pride

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			Action	DRS
	3383_4-21-2022_Castillo_14461_DIA_140min_6ul_RB1.d.zip	Other
	3384_4-21-2022_Castillo_14463_DIA_140min_6ul_RB2.d.zip	Other
	3385_4-21-2022_Castillo_14465_DIA_140min_6ul_RB3.d.zip	Other
	3386_4-22-2022_Castillo_14467_DIA_140min_6ul_RB4.d.zip	Other
	3389_4-22-2022_Castillo_14462_DIA_140min_6ul_RB5.d.zip	Other

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Project description:Objective: Athletes increasingly engage in repeated sprint training that consists of repeated short all-out effort interspersed by short periods of recovery. When performed in hypoxia (RSH), it may lead to greater training effects than in normoxia (RSN), however the underlying molecular mechanisms remain unclear. This study aimed at elucidating the effects of RSH on skeletal muscle oxidative and glycolytic adaptations as compared to RSN. Methods: Healthy young men performed nine repeated sprint training sessions in three weeks. Each training session consisted in six series of six sprints in either normoxia (FiO2 = 20.9%, RSN, n = 7) or normobaric hypoxia (FiO2 = 13.6%, RSH, n = 9). Before and after the training period, exercise performance was assessed by using repeated sprint ability (RSA) and Wingate tests. Vastus lateralis muscle biopsies were performed to investigate muscle metabolic adaptations using proteomic combined to western blotting analyses. Results: We observed similar improvements in RSA and Wingate tests in both RSH and RSN groups. Proteomic analysis revealed a decrease in several proteins involved in oxidative phosphorylation (OXPHOS) in both groups and this was confirmed with western blot showing significant reductions in complexes I and V protein levels. RSN and RSH increased protein levels of the glycolytic enzyme hexokinase II, while only RSH induced a significant increase in the glucose transporter 4 (GLUT4) protein levels, suggesting superior glycolytic adaptations in response to hypoxia. This phenotype is further supported by proteomics data showing significant increase of proteins involved in glycolysis. Our proteomics data showed in the RSH group a specific increase in several S100A family proteins, among which S100A13 was the most modified, a result confirmed by western blot. S100A proteins have recently been shown to accelerate glycolytic phenotype of cancer cells by activating the protein kinase B (Akt) pathway. Our data corroborate these findings by showing in RSH group increased Akt phosphorylation as well as increased levels of proteins related to Akt downstream effects such as enhanced translation. Conclusions: Altogether our data indicate that RSH, as compared to RSN, potentiates the muscle glycolytic phenotype, possibly through the activation of S100A13 and the Akt pathway.

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Repeated hypoglycemia in diabetic mice induce hypothalamic mitochondrial and synaptic activity deregulations characteristic of neurodegenerative diseases

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